tbuckley/cabot-search huggingface dataset:
Self‐Assembled Carrier‐Free Nanodrugs for Starvation Therapy‐Amplified Photodynamic Therapy of Cancer
Authors: Dong‐Yang Zhang, Yuqin Liang, Mingcheng Wang, Muhammad Rizwan Younis, Huixi Yi, Xiaoya Zhao, Jishuo Chang, Yue Zheng, Weisheng Guo, Xiyong Yu
Journal: Advanced Healthcare Materials (2023)

Traditional starvation treatment strategies, which involve glucose oxidase and drug-induced thrombi, often suffer from aggravated tumor hypoxia and have failed to improve antitumor efficacy in combination with oxygen-dependent photodynamic therapy (PDT). Herein, glucose transporter 1 inhibitor genistein (Gen) and photosensitizer chlorin e6 (Ce6) are integrated to construct carrier-free self-assembled nanoparticles defined as GC NPs, for starvation therapy-amplified PDT of tumor. GC NPs with regular morphology and stability are screened out by component adjustment, while the function of each component is preserved. On the one hand, Gen released from GC NPs can cut off tumor glucose uptake by inhibiting the glucose transporter 1 to restrict tumor growth, achieving starvation therapy. On the other hand, they are able to decrease the amount of oxygen consumed by tumor respiration and amplify the therapeutic effect of PDT. In vitro and in vivo experiments verify the excellent synergistic antitumor therapeutic efficacy of GC NPs without any apparent toxicity. Moreover, fluorescence and photoacoustic imaging provide guidance for in vivo PDT, demonstrating the excellent tumor enrichment efficiency of GC NPs. It is believed that this starvation therapy-amplified PDT strategy by carrier-free self-assembled GC NPs holds promising clinical prospects.
Assessment of the Effectiveness of Knee Joints Treatment With the Use of 90Y
Authors: Olgierd Chrabański, Ewa Kluczewska, Tomasz Gołąb, Izabela Gorczewska
Journal: Clinical Nuclear Medicine (2023)

Purpose The purpose of this prospective study was to assess the effectiveness of knee joints treatment by radiosynoviorthesis with the use of 90 Y based on ultrasound and clinical analysis. Materials and Methods Ninety-seven patients were qualified for treatment from October 2016 to June 2017, and observation period lasted until December 2017. Bioethics Committee of the Medical University of Silesia approved this study. The effectiveness of knee joints treatment with the use of 90 Y was based on 927 ultrasound measurements of fluid and 927 synovial thickness in 3 sites of the suprapatellar recess, 309 assessments of patient’s disability documented in Lequesne questionnaire, 309 assessments of pain on visual analog scale, as well as 103 overall self-assessment. Statistical methods were used to process the results. Results A reduction in fluid was found in 62.14% of the knees; synovial thickness reduction was observed in 97.09% of all knees. The greatest benefit from the therapy was experienced by patients complaining of morning stiffness lasting more than 15 minutes (in 85.71% of joints). There was reduction in pain at rest in 94.52% of knee joints and in 80.39% of joints with pain while walking. At the second follow-up visit after treatment, the percentage of improvement in self-assessment was 74.76%. Conclusions Statistically significant decreases in the amount of fluid and thickness of the synovial membrane as well as the level of disability and the intensity of pain after radiosynoviorthesis 90 Y treatment were demonstrated.
Targeting<i>NRAS</i>Mutations in Advanced Melanoma
Authors: Manali S. Phadke, Keiran S.M. Smalley
Journal: Journal of Clinical Oncology (2023)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Initial Evidence for the Efficacy of Naporafenib in Combination With Trametinib in NRAS-Mutant Melanoma: Results From the Expansion Arm of a Phase Ib, Open-Label Study. March 22, 2023 ARTICLE CITATION DOI: 10.1200/JCO.23.00205 Journal of Clinical Oncology - published online before print March 22, 2023 PMID: 36947724 Targeting NRAS Mutations in Advanced Melanoma Manali S. Phadke, PhD1xManali S. PhadkeSearch for articles by this author and Keiran S.M. Smalley , PhD1,2xKeiran S.M. SmalleySearch for articles by this author Show More 1Department of Tumor Biology, Moffitt Cancer Center & Research Institute, Tampa, FL2Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL https://doi.org/10.1200/JCO.23.00205 First Page Full Text PDF Figures and Tables © 2023 by American Society of Clinical OncologySUPPORTSupported by the National Cancer Institute (R01 CA256193, R01 CA262483, R21 CA256289, R21 CA267141) and the Melanoma Research Foundation and Revolution Medicines.AUTHOR CONTRIBUTIONSConception and design: Keiran S.M. SmalleyCollection and assembly of data: Manali S. PhadkeManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authorsAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTTargeting NRAS Mutations in Advanced MelanomaThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Keiran S.M. SmalleyResearch Funding: Revolution Medicines (Inst)No other potential conflicts of interest were reported. Companion Initial Evidence for the Efficacy of Naporafenib in Combination With Trametinib in NRAS-Mutant Melanoma: Results From the Expansion Arm of a Phase Ib, Open-Label Study
Inhibition of a signaling modality within the gp130 receptor enhances tissue regeneration and mitigates osteoarthritis
Authors: Ruzanna Shkhyan, Candace Flynn, Emma Lamoure, Arijita Sarkar, Benjamin Van Handel, Jinxiu Li, Jesse York, Nicholas Banks, Robert Van der Horst, Nancy Q. Liu, Siyoung Lee, Paul Bajaj, Kanagasabai Vadivel, Hans I.-Chen Harn, Jade Tassey, Thomas Lozito, Jay R. Lieberman, Cheng-Ming Chuong, Mark S. Hurtig, Denis Evseenko
Journal: Science Translational Medicine (2023)

Adult mammals are incapable of multitissue regeneration, and augmentation of this potential may shift current therapeutic paradigms. We found that a common co-receptor of interleukin 6 (IL-6) cytokines, glycoprotein 130 (gp130), serves as a major nexus integrating various context-specific signaling inputs to either promote regenerative outcomes or aggravate disease progression. Via genetic and pharmacological experiments in vitro and in vivo, we demonstrated that a signaling tyrosine 814 (Y814) within gp130 serves as a major cellular stress sensor. Mice with constitutively inactivated Y814 (F814) were resistant to surgically induced osteoarthritis as reflected by reduced loss of proteoglycans, reduced synovitis, and synovial fibrosis. The F814 mice also exhibited enhanced regenerative, not reparative, responses after wounding in the skin. In addition, pharmacological modulation of gp130 Y814 upstream of the SRC and MAPK circuit by a small molecule, R805, elicited a protective effect on tissues after injury. Topical administration of R805 on mouse skin wounds resulted in enhanced hair follicle neogenesis and dermal regeneration. Intra-articular administration of R805 to rats after medial meniscal tear and to canines after arthroscopic meniscal release markedly mitigated the appearance of osteoarthritis. Single-cell sequencing data demonstrated that genetic and pharmacological modulation of Y814 resulted in attenuation of inflammatory gene signature as visualized by the anti-inflammatory macrophage and nonpathological fibroblast subpopulations in the skin and joint tissue after injury. Together, our study characterized a molecular mechanism that, if manipulated, enhances the intrinsic regenerative capacity of tissues through suppression of a proinflammatory milieu and prevents pathological outcomes in injury and disease.
The enhancer landscape predetermines the skeletal regeneration capacity of stromal cells
Authors: Sarah Hochmann, Kristy Ou, Rodolphe Poupardin, Michaela Mittermeir, Martin Textor, Salaheddine Ali, Martin Wolf, Agnes Ellinghaus, Dorit Jacobi, Juri A. J. Elmiger, Samantha Donsante, Mara Riminucci, Richard Schäfer, Uwe Kornak, Oliver Klein, Katharina Schallmoser, Katharina Schmidt-Bleek, Georg N. Duda, Julia K. Polansky, Sven Geissler, Dirk Strunk
Journal: Science Translational Medicine (2023)

Multipotent stromal cells are considered attractive sources for cell therapy and tissue engineering. Despite numerous experimental and clinical studies, broad application of stromal cell therapeutics is not yet emerging. A major challenge is the functional diversity of available cell sources. Here, we investigated the regenerative potential of clinically relevant human stromal cells from bone marrow (BMSCs), white adipose tissue, and umbilical cord compared with mature chondrocytes and skin fibroblasts in vitro and in vivo. Although all stromal cell types could express transcription factors related to endochondral ossification, only BMSCs formed cartilage discs in vitro that fully regenerated critical-size femoral defects after transplantation into mice. We identified cell type–specific epigenetic landscapes as the underlying molecular mechanism controlling transcriptional stromal differentiation networks. Binding sites of commonly expressed transcription factors in the enhancer and promoter regions of ossification-related genes, including Runt and bZIP families, were accessible only in BMSCs but not in extraskeletal stromal cells. This suggests an epigenetically predetermined differentiation potential depending on cell origin that allows common transcription factors to trigger distinct organ-specific transcriptional programs, facilitating forward selection of regeneration-competent cell sources. Last, we demonstrate that viable human BMSCs initiated defect healing through the secretion of osteopontin and contributed to transient mineralized bone hard callus formation after transplantation into immunodeficient mice, which was eventually replaced by murine recipient bone during final tissue remodeling.
Desmosomal protein degradation as an underlying cause of arrhythmogenic cardiomyopathy
Authors: Hoyee Tsui, Sebastiaan Johannes van Kampen, Su Ji Han, Viviana Meraviglia, Willem B. van Ham, Simona Casini, Petra van der Kraak, Aryan Vink, Xiaoke Yin, Manuel Mayr, Alexandre Bossu, Gerard A. Marchal, Jantine Monshouwer-Kloots, Joep Eding, Danielle Versteeg, Hesther de Ruiter, Karel Bezstarosti, Judith Groeneweg, Sjoerd J. Klaasen, Linda W. van Laake, Jeroen A.A. Demmers, Geert J.P.L. Kops, Christine L. Mummery, Toon A.B. van Veen, Carol Ann Remme, Milena Bellin, Eva van Rooij
Journal: Science Translational Medicine (2023)

Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiac disease. Many patients with ACM harbor mutations in desmosomal genes, predominantly in plakophilin-2 ( PKP2 ). Although the genetic basis of ACM is well characterized, the underlying disease-driving mechanisms remain unresolved. Explanted hearts from patients with ACM had less PKP2 compared with healthy hearts, which correlated with reduced expression of desmosomal and adherens junction (AJ) proteins. These proteins were also disorganized in areas of fibrotic remodeling. In vitro data from human-induced pluripotent stem cell–derived cardiomyocytes and microtissues carrying the heterozygous PKP2 c.2013delC pathogenic mutation also displayed impaired contractility. Knockin mice carrying the equivalent heterozygous Pkp2 c.1755delA mutation recapitulated changes in desmosomal and AJ proteins and displayed cardiac dysfunction and fibrosis with age. Global proteomics analysis of 4-month-old heterozygous Pkp2 c.1755delA hearts indicated involvement of the ubiquitin-proteasome system (UPS) in ACM pathogenesis. Inhibition of the UPS in mutant mice increased area composita proteins and improved calcium dynamics in isolated cardiomyocytes. Additional proteomics analyses identified lysine ubiquitination sites on the desmosomal proteins, which were more ubiquitinated in mutant mice. In summary, we show that a plakophilin-2 mutation can lead to decreased desmosomal and AJ protein expression through a UPS-dependent mechanism, which preceded cardiac remodeling. These findings suggest that targeting protein degradation and improving desmosomal protein stability may be a potential therapeutic strategy for the treatment of ACM.
An ASO therapy for Angelman syndrome that targets an evolutionarily conserved region at the start of the <i>UBE3A-AS</i> transcript
Authors: Scott V. Dindot, Sarah Christian, William J. Murphy, Allyson Berent, Jennifer Panagoulias, Annalise Schlafer, Johnathan Ballard, Kamelia Radeva, Ruth Robinson, Luke Myers, Thomas Jepp, Hillary Shaheen, Paul Hillman, Kranti Konganti, Andrew Hillhouse, Kevin R. Bredemeyer, Lauren Black, Julie Douville, Edwin Weeber, David Segal, Anne Anderson, Kevin Nash, Jill Silverman
Journal: Science Translational Medicine (2023)

Angelman syndrome is a devastating neurogenetic disorder for which there is currently no effective treatment. It is caused by mutations or epimutations affecting the expression or function of the maternally inherited allele of the ubiquitin-protein ligase E3A ( UBE3A ) gene. The paternal UBE3A allele is imprinted in neurons of the central nervous system (CNS) by the UBE3A antisense ( UBE3A-AS ) transcript, which represents the distal end of the small nucleolar host gene 14 ( SNHG14 ) transcription unit. Reactivating the expression of the paternal UBE3A allele in the CNS has long been pursued as a therapeutic option for Angelman syndrome. Here, we described the development of an antisense oligonucleotide (ASO) therapy for Angelman syndrome that targets an evolutionarily conserved region demarcating the start of the UBE3A-AS transcript. We designed and chemically optimized gapmer ASOs targeting specific sequences at the start of the human UBE3A-AS transcript. We showed that ASOs targeting this region precisely and efficiently repress the transcription of UBE3A-AS , reactivating the expression of the paternal UBE3A allele in neurotypical and Angelman syndrome induced pluripotent stem cell–derived neurons. We further showed that human-targeted ASOs administered to the CNS of cynomolgus macaques by lumbar intrathecal injection repress UBE3A-AS and reactivate the expression of the paternal UBE3A allele throughout the CNS. These findings support the advancement of this investigational molecular therapy for Angelman syndrome into clinical development ( ClinicalTrials.gov , NCT04259281).
Antibody-mediated protection against symptomatic COVID-19 can be achieved at low serum neutralizing titers
Authors: Pete Schmidt, Kristin Narayan, Yong Li, Chengzi I. Kaku, Michael E. Brown, Elizabeth Champney, James C. Geoghegan, Maximiliano Vásquez, Eric M. Krauland, Thomas Yockachonis, Shuangyi Bai, Bronwyn M. Gunn, Anthony Cammarata, Christopher M. Rubino, Paul Ambrose, Laura M. Walker
Journal: Science Translational Medicine (2023)

Multiple studies of vaccinated and convalescent cohorts have demonstrated that serum neutralizing antibody (nAb) titers correlate with protection against coronavirus disease 2019 (COVID-19). However, the induction of multiple layers of immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure has complicated the establishment of nAbs as a mechanistic correlate of protection (CoP) and hindered the definition of a protective nAb threshold. Here, we show that a half-life–extended monoclonal antibody (adintrevimab) provides about 50% protection against symptomatic COVID-19 in SARS-CoV-2–naïve adults at serum nAb titers on the order of 1:30. Vaccine modeling results support a similar 50% protective nAb threshold, suggesting that low titers of serum nAbs protect in both passive antibody prophylaxis and vaccination settings. Extrapolation of adintrevimab pharmacokinetic data suggests that protection against susceptible variants could be maintained for about 3 years. The results provide a benchmark for the selection of next-generation vaccine candidates and support the use of broad, long-acting monoclonal antibodies as alternatives or supplements to vaccination in high-risk populations.
Three-Dimensional Sulfated Bacterial Cellulose/Gelatin Composite Scaffolds for Culturing Hepatocytes
Authors: Xinmeng Li, Weixiao Ding, Shujun Wang, Luyu Yang, Qingqing Yu, Changji Xiao, Guangbo Chen, Lei Zhang, Shanyue Guan, Dongping Sun
Journal: Cyborg and Bionic Systems (2023)

The liver is the hub of human metabolism and involves many diseases. To better work on the mechanism and treatment of liver diseases, it is of particular interest to design 3-dimensional scaffolds suitable for culturing hepatocytes in vitro to simulate their metabolic and regenerative abilities. In this study, sulfated bacterial cellulose (SBC) was prepared as the building block of cell scaffolds, motivated by the anionic nature and 3-dimensional structure of hepatic extracellular matrix, and its reaction condition for sulfate esterification was optimized by changing the reaction time. The analysis and study of the microscopic morphology, structure, and cytocompatibility of SBCs showed that they possess good biocompatibility and meet the requirements for tissue engineering. Next, SBC was mixed with gelatin for composite scaffolds (SBC/Gel) for culturing hepatocytes by homogenization and freeze-drying methods, whose physical properties such as pore size, porosity, and compression properties were compared with gelatin (Gel) scaffolds as the control group, and the cytological activity and hemocompatibility of the composite scaffolds were investigated. The results showed that the SBC/Gel composite has better porosity and compression properties, as well as good cytocompatibility and hemocompatibility, and could be applied to 3-dimensional culture of hepatocytes for drug screening or liver tissue engineering.
Inhaled pirfenidone solution (AP01) for IPF: a randomised, open-label, dose–response trial
Authors: Alex West, Nazia Chaudhuri, Adam Barczyk, Margaret L Wilsher, Peter Hopkins, Ian Glaspole, Tamera Jo Corte, Martina Šterclová, Antony Veale, Ewa Jassem, Marlies S Wijsenbeek, Christopher Grainge, Wojciech Piotrowski, Ganesh Raghu, Michele L Shaffer, Deepthi Nair, Lisa Freeman, Kelly Otto, A Bruce Montgomery
Journal: Thorax (2023)

Oral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects, including nausea, rash, photosensitivity, weight loss and fatigue. Reduced doses may be suboptimal in slowing disease progression.This phase 1b, randomised, open-label, dose-response trial at 25 sites in six countries (Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12618001838202) assessed safety, tolerability and efficacy of inhaled pirfenidone (AP01) in IPF. Patients diagnosed within 5 years, with forced vital capacity (FVC) 40%-90% predicted, and intolerant, unwilling or ineligible for oral pirfenidone or nintedanib were randomly assigned 1:1 to nebulised AP01 50 mg once per day or 100 mg two times per day for up to 72 weeks.We present results for week 24, the primary endpoint and week 48 for comparability with published trials of antifibrotics. Week 72 data will be reported as a separate analysis pooled with the ongoing open-label extension study. Ninety-one patients (50 mg once per day: n=46, 100 mg two times per day: n=45) were enrolled from May 2019 to April 2020. The most common treatment-related adverse events (frequency, % of patients) were all mild or moderate and included cough (14, 15.4%), rash (11, 12.1%), nausea (8, 8.8%), throat irritation (5, 5.5%), fatigue (4, 4.4%) and taste disorder, dizziness and dyspnoea (three each, 3.3%). Changes in FVC % predicted over 24 and 48 weeks, respectively, were -2.5 (95% CI -5.3 to 0.4, -88 mL) and -4.9 (-7.5 to -2.3,-188 mL) in the 50 mg once per day and 0.6 (-2.2 to 3.4, 10 mL) and -0.4 (-3.2 to 2.3, -34 mL) in the 100 mg two times per day group.Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01. Mean FVC % predicted remained stable in the 100 mg two times per day group. Further study of AP01 is warranted.ACTRN12618001838202 Australian New Zealand Clinical Trials Registry.
Randomised controlled trial for the titration of oral corticosteroids using markers of inflammation in severe asthma
Authors: J Michael Ramsahai, Jodie L Simpson, Alistair Cook, Peter G Gibson, Vanessa McDonald, Christopher Grainge, Liam G Heaney, Peter AB Wark
Journal: Thorax (2023)

Introduction Biomarkers are used to select biologic therapies for patients with severe asthma, but not to regularly adjust therapy, especially oral corticosteroids (OCS). Objective Our goal was to test the efficacy of an algorithm to guide the titration of OCS using blood eosinophil count and fraction of exhaled nitric oxide (FeNO) levels. Design, participants, interventions and setting This proof-of-concept prospective randomised controlled trial assigned adult participants with severe uncontrolled asthma (n=32) to biomarker-based management (BBM) where OCS dose was adjusted based on a composite biomarker score comprised of blood eosinophil count and FeNO, or a standard best practice (SBP) arm. The study was conducted at the Hunter Medical Research Institute, Newcastle, Australia. Participants were recruited from the local Severe Asthma Clinic and were blinded to their study allocation. Main outcome The coprimary outcomes were number of severe exacerbations and time to first severe exacerbation assessed over 12 months. Results There was a longer median time to first severe exacerbation with BBM, although not significant (295 vs 123 days, Adj. HR: 0.714; 95% CI: 0.25 to 2.06; p=0.533). The relative risk of a severe exacerbation in BBM (n=17) vs SBP (n=15) was 0.88 (Adj.; 95% CI: 0.47 to 1.62; p=0.675) with a mean exacerbation rate per year of 1.2 and 2.0, respectively. There was a significant reduction in the proportion of patients requiring an emergency department (ED) visit using BBM (OR 0.09, 95% CI: 0.01 to 0.91; p=0.041). There was no difference in the cumulative OCS dose used between the two groups. Conclusion A treatment algorithm to adjust OCS using blood eosinophil count and FeNO is feasible in a clinical setting and resulted in a reduced odds of an ED visit. This warrants further study to optimise the use of OCS in the future. Trial registration number This trial was registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12616001015437).